Glaser T, Winter S, Groscurth P, Safayhi H, Sailer E R, Ammon H P, Schabet M, Weller M
Department of Neurology, University of Tübingen, Germany.
Br J Cancer. 1999 May;80(5-6):756-65. doi: 10.1038/sj.bjc.6690419.
Steroids are essential for the control of oedema in human malignant glioma patients but may interfere with the efficacy of chemotherapy. Boswellic acids are phytotherapeutic anti-inflammatory agents that may be alternative drugs to corticosteroids in the treatment of cerebral oedema. Here, we report that boswellic acids are cytotoxic to malignant glioma cells at low micromolar concentrations. In-situ DNA end labelling and electron microscopy reveal that boswellic acids induce apoptosis. Boswellic acid-induced apoptosis requires protein, but not RNA synthesis, and is neither associated with free radical formation nor blocked by free radical scavengers. The levels of BAX and BCL-2 proteins remain unaltered during boswellic acid-induced apoptosis. p21 expression is induced by boswellic acids via a p53-independent pathway. Ectopic expression of wild-type p53 also induces p21, and facilitates boswellic acid-induced apoptosis. However, targeted disruption of the p21 genes in colon carcinoma cells enhances rather than decreases boswellic acid toxicity. Ectopic expression of neither BCL-2 nor the caspase inhibitor, CRM-A, is protective. In contrast to steroids, subtoxic concentrations of boswellic acids do not interfere with cancer drug toxicity of glioma cells in acute cytotoxicity or clonogenic cell death assays. Also, in contrast to steroids, boswellic acids synergize with the cytotoxic cytokine, CD95 ligand, in inducing glioma cell apoptosis. This effect is probably mediated by inhibition of RNA synthesis and is not associated with changes of CD95 expression at the cell surface. Further studies in laboratory animals and in human patients are required to determine whether boswellic acids may be a useful adjunct to the medical management of human malignant glioma.
类固醇对于控制人类恶性胶质瘤患者的水肿至关重要，但可能会干扰化疗效果。乳香酸是植物治疗性抗炎剂，在治疗脑水肿方面可能是皮质类固醇的替代药物。在此，我们报告乳香酸在低微摩尔浓度下对恶性胶质瘤细胞具有细胞毒性。原位DNA末端标记和电子显微镜显示乳香酸诱导细胞凋亡。乳香酸诱导的细胞凋亡需要蛋白质合成，但不需要RNA合成，且既不与自由基形成相关，也不受自由基清除剂的阻断。在乳香酸诱导的细胞凋亡过程中，BAX和BCL-2蛋白水平保持不变。乳香酸通过p53非依赖途径诱导p21表达。野生型p53的异位表达也诱导p21，并促进乳香酸诱导的细胞凋亡。然而，结肠癌细胞中p21基因的靶向破坏增强而非降低乳香酸毒性。BCL-2和半胱天冬酶抑制剂CRM-A的异位表达均无保护作用。与类固醇不同，乳香酸的亚毒性浓度在急性细胞毒性或克隆形成细胞死亡试验中不干扰胶质瘤细胞的抗癌药物毒性。此外，与类固醇不同，乳香酸与细胞毒性细胞因子CD95配体协同诱导胶质瘤细胞凋亡。这种效应可能是由RNA合成的抑制介导的，且与细胞表面CD95表达的变化无关。需要在实验动物和人类患者中进行进一步研究，以确定乳香酸是否可能是人类恶性胶质瘤医学管理的有用辅助药物。
